Tumor-intrinsic features associated with progression-free survival (PFS) in patients (pts) with relapsed and refractory multiple myeloma (RRMM) treated with idecabtagene vicleucel (ide-cel).
Authors: Nicholas Stong, Ethan Thompson, Amy Xu, Julie Rytlewski, Arnaud Amzallag, Timothy Brandon Campbell, Sundar Jagannath, Nikhil C. Munshi, Julia Piasecki, Debashree Basudhar, Maria Ortiz Estevez, Shari Kaiser, Erin Flynt, Nathan Martin
Journal: Journal of Clinical Oncology (2023)

8035 Background: Ide-cel, a B-cell maturation antigen chimeric antigen receptor T cell therapy, has demonstrated frequent, deep, and durable responses in pts with RRMM in the KarMMa (NCT03361748), KarMMa-2 (NCT03601078), and KarMMa-3 (NCT03651128) trials. A previous analysis of KarMMa showed comparable efficacy of ide-cel across molecular high-risk/resistance (HR/R) features such as biallelic p53 inactivation, 1q amplification, t(4;14), and CRBN dysregulation, and identified a baseline gene expression pattern (PC4) associated with PFS (Martin N, et al. Hemasphere 2022;6:(S6):1452). We aim to identify additional genomic features associated with ide-cel efficacy in KarMMa and KarMMa-2, and evaluate samples from KarMMa-3 pts as an independent validation cohort. Methods: Transcriptional and genomic profiles were assessed at baseline in CD138+ cells from bone marrow from pts in KarMMa, KarMMa-2 cohort 1, and KarMMa-3. Gene copy number aberrations were evaluated for associations with response. Analyses were post hoc and exploratory, and a P-value, or false discovery rate (FDR), of &lt; 0.05 was used to identify associations of interest. Results: In evaluable pts in KarMMa (n = 70), single copy number loss was observed at 2 loci that associated with PFS, a broad region across 14q (n = 16) and deletion at 1p31.2 (n = 6). These were generally independent and collectively represented 30% (21/70) of pts. Both were associated with shorter median PFS (mPFS) in KarMMa (cohort mPFS, 8.8 mo, n = 128; Munshi et al. N Engl J Med 2021;384:705-16) after FDR correction (del 14q, mPFS, 4.0 mo; del 1p31.2, mPFS, 2.3 mo). No pt with 1p loss achieved a best overall response (BOR) better than partial response. Pts with loss vs non-loss of 14q had similar BOR distribution, but poorer mPFS within each BOR (10.4 vs 29.7 mo for loss vs non-loss in pts with complete response/stringent complete response). Due to small sample size in KarMMa-2 cohort 1 (n = 18), these data were aggregated with those from KarMMa. When combined, previously described associations with HR/R features were maintained except for biallelic p53 inactivation, which showed a stronger association with shorter PFS in the aggregate dataset (n = 83, P = 0.04) than in KarMMa (n = 65, P = 0.09). KarMMa-3 (n = 210) analysis is ongoing and will be used as a validation cohort for these findings. Consistent trends for the association of the PC4 gene signature with PFS were observed in KarMMa-2 but were not statistically significant and limited by sample size. Conclusions: Two novel genomic HR/R features associated with PFS were identified using samples from KarMMa; validation is ongoing using samples from KarMMa-3. The PC4 gene signature was consistent in 2 RRMM cohorts. A modest association between biallelic p53 disruption and PFS emerged with increased sample size and will be studied in KarMMa-3.